Histological Necrosis Research Articles

A case report of metastatic renal oncocytoma

Introduction Renal oncocytomas are renal tumours that are largely considered to be benign. They represent 5.5% of all renal tumours and the age-standardised incidence is 0.3 per 100,000/year in men and women.1 Despite this, there have been reported cases where these tumours have developed metastases. We report the case of a patient who had a right radical nephrectomy for renal oncocytoma who then presents nine years later with a pathological neck of femur (NOF) fracture secondary to metastases, suggesting malignant behaviour of the tumour. Case description A 62-year-old lady presented in December 2010 with shortness of breath on exertion, frontal headache and malignant hypertension. She was treated with Ramipril and her blood pressure subsided. On discharge she underwent further investigations, including 24hour urine catecholamine test – (normal), and abdominal ultrasound which revealed a mass in the right kidney. Computerized tomography (CT) confirmed a well-defined lower pole right renal solid mass measuring 7.5x5.7cm, extending to the renal pelvis with compression of the vascular pedicle. There was no evidence of extrarenal extension. Renal cell carcinoma stage T2 was suggested. She underwent a right laparoscopic nephrectomy and recovered well from the operation. Histology confirmed oncocytoma with atypical features of extrarenal invasion, absence of Hale’s colloidal blue staining, negativity for cytokeratin 7 and positive vimentin staining. This patient had yearly follow-up CT. Four years after her first surgery, a nodule was noted in the right nephrectomy bed. Surgical excision confirmed recurrent oncocytoma. Two years after this she presented with pathological fracture of her right neck of femur. A bone biopsy confirmed metastatic disease. She had a dynamic hip screw fixation. Results and Conclusions The World Health Organization classifies renal oncocytoma as benign neoplasm.2 Nevertheless there are case reports of metastatic disease in these tumours. Studies have revealed a classical pattern with typical features of benign neoplasia in 57.5-67% of cases. Malignant features such as atypical histological pattern, focal necrosis, multinucleation, mitotic activity, degenerative atypia and invasion of extrarenal fat have been described in others. Despite this, not all patients with such features progress to developing metastatic disease at 5-year follow-up. In fact only 2 patients out of 42 with atypical features developed metastatic disease.3 This suggests that there is a potential for metastatic transformation of this tumour, especially in the group with features of atypia. There is a however, paucity of information in published literature regarding this. The risk stratification of these atypical features will be a good start. Clearly, further research by way of genetic assessment, including chromosomal and tumour markers is required, as part of future diagnosis and management algorithm. Take home message Metastatic renal oncocytomas are extremely rare. Little is known about the atypical features that predispose metastatic transformation. Our patient developed local recurrence and a distant metastatic lesion with fracture neck of femur 6 years later. Our extensive search of literature has shown only 2 other reported cases of metastatic oncocytomas in the bone being the tibia and femur. The patient with the femoral fracture had multiple bone metastatic lesions. Further research into the biological features and characteristics of this extremely rare condition is required. This may help stratifying patients into metastatic risk potentials. Perhaps treatment plans can be tailored accordingly.

Intracranial melanotic schwannomas: a rare variant with unusual adherent features.

Intracranial melanotic schwannomas (IMSch) are extremely rare nerve sheath tumors with features of Schwann cells that produce melanin. After a thorough review of the available literature since 1967, we report not only the 20th case of IMSch but a comprehensive modern-era analysis of radiographic and histological key-points to be considered when diagnosing and treating patients with this rare known entity. This is the case of a 43 years-old woman who presented with severe headaches 9 years ago (2008). At that time, MRI of the brain showed a 1.5 × 1.4cm lesion at the level of the left cerebellar peduncle without any evidence of edema, mass effect or hydrocephalus. Given that the patient was neurologically intact, a conservative management with serial MRIs was recommended. Patient stopped following up due to the absence of symptoms. Over the course of the past year, patient noted mild left sided hearing loss and facial weakness, as well as some balance instability that progressed over the last 3 months. Given the presentation and progression of these signs and symptoms, a new MRI was performed in which considerable growth of the lesion was identified, measuring 2.5 × 2.8 × 2.6cm with mass effect on the pons and the inferior fourth ventricle. She underwent a far lateral approach without a C1 hemilaminectomy for the resection of this lesion. Final pathology was consistent with a non-psammomatous melanotic schwannoma (NPMS) with areas of necrosis. Besides this case, only two other cases of IMSch with findings of necrosis have been reported in the literature, all of them reporting a subtotal resection. Evaluation of all previously reported cases of IMSch shows a male prevalence with a 1.6:1 male to female ratio. IMSch is radiographically T2 hypointense and can be differentiated from Schwannomas that are classically T2 hyperintense. In this case, only a subtotal resection was feasible due to the tumor's overwhelming inherent attachment to vital structures such as cranial nerves (CN), brainstem, and vasculature. While MSch is considered histologically benign, several factors including localization, surrounding structures, the rate of growth, tumor volume resection and histological necrosis should be considered in determining prognosis and further adjuvant treatment planning.

Volume fractions of DCE-MRI parameter as early predictor of histologic response in soft tissue sarcoma: A feasibility study

ObjectiveTo find early predictors of histologic response in soft tissue sarcoma through volume transfer constant (Ktrans) analysis based on dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). Materials and methods11 Patients with soft tissue sarcoma of the lower extremity that underwent preoperative chemoradiotherapy followed by limb salvage surgery were included in this retrospective study. For each patient, DCE-MRI data sets were collected before and two weeks after therapy initiation, and histologic tumor cell necrosis rate (TCNR) was reported at surgery. The DCE-MRI volumes were aligned by registration. Then, the aligned volumes were used to obtain the Ktrans variation map. Accordingly, three sub-volumes (with increased, decreased or unchanged Ktrans) were defined and identified, and fractions of the sub-volumes, denoted as F+, F- and F0, respectively, were calculated. The predictive ability of volume fractions was determined by using area under a receiver operating characteristic curve (AUC). Linear regression analysis was performed to investigate the relationship between TCNR and volume fractions. In addition, the Ktrans values of the sub-volumes were compared. ResultsThe AUC for F- (0.896) and F0 (0.833) were larger than that for change of tumor longest diameter ΔD (0.625) and the change of mean KtransΔKtrans¯ (0.792). Moreover, the regression results indicated that TCNR was directly proportional to F0 (R2=0.75, P=0.0003), while it was inversely proportional to F- (R2=0.77, P=0.0002). However, TCNR had relatively weak linear relationship with ΔKtrans¯ (R2=0.64, P=0.0018). Additionally, TCNR did not have linear relationship with DD (R2=0.16, P=0.1246). ConclusionThe volume fraction F- and F0 have potential as early predictors of soft tissue sarcoma histologic response.

Blood Platelet Volume Represents a Novel Prognostic Factor in Patients with Nonmetastatic Renal Cell Carcinoma and Improves the Predictive Ability of Established Prognostic Scores.

The average size of blood platelets determined by mean platelet volume might represent a biologically meaningful parameter in carcinogenesis and potentially serve as a novel prognostic biomarker in renal cell carcinoma. In this retrospective analysis of the records of 652 patients we evaluated the potential prognostic value of mean platelet volume and its ability to improve existing risk assessment tools used in adjuvant clinical trials in nonmetastatic renal cell carcinoma cases. Associations of mean platelet volume with baseline covariates and clinical outcomes (recurrence, and death from renal cell carcinoma and other causes) were assessed with the competing risk estimators of Kaplan-Meier, and Marubini and Valsecchi, respectively. Univariable and multivariable Cox proportional hazard models were constructed. The Harrell c-index was applied to test improvements in the predictive accuracy of the established Leibovich prognosis score. Small platelet volume was associated with large tumors (p = 0.043), high Fuhrman grade (p = 0.001), sarcomatoid components (p <0.0001), histological tumor necrosis (p = 0.044) and vascular invasion (p = 0.022). On univariable and multivariable analyses small platelet volume accurately predicted recurrent renal cell carcinoma (continuously and binary coded) and cancer specific survival. Adding mean platelet volume to the Leibovich prognosis score improved its discriminative performance (c-index = 0.83, p = 0.004). Mean platelet volume represented a highly significant predictor of recurrence and cancer specific death in patients with renal cell carcinoma. This parameter improved the accuracy of the Leibovich prognosis score to better predict long-term outcomes in localized renal cell carcinoma cases after curative surgical resection.

Tumor necrosis and infiltrating macrophages predict survival after curative resection for cholangiocarcinoma

ABSTRACTBackground. Tumor necrosis as well as tumor-associated macrophages (TAMs) in the tumor invasive front (TIF) have been suggested to have a prognostic value in selected solid tumors, inclusive hilar cholangiocarcinoma. However, little is known regarding their influence on tumor progression and prognosis in intrahepatic cholangiocarcinoma (iCC).Methods. We analyzed surgically resected tumor specimens of human iCC (n = 88) for distribution and localization of TAMs, as defined by expression of CD68, formation of necrosis and extent of peritumoral fibrosis. Abundance of TAMs, tumor necrosis and grade of fibrosis were assessed immunohistochemically and histologically and correlated with clinicopathological characteristics, tumor recurrence and patients' survival. Statistical analysis was performed using SPSS software.Results. Patients with tumors characterized by low levels of TAMs in TIF or necrosis showed a significantly decreased 1-, 3- and 5-y recurrence-free survival and a significantly decreased overall survival, when compared with patients with tumors showing high levels of TAMs in TIF or no necrosis. Patients with high density of TAMs in TIF showed significantly lower incidence of tumor recurrence, as well (p < 0.05). Absence of tumor necrosis and TAMs in TIF were confirmed as independent prognostic variables in the multivariate survival analysis (all p < 0.05).Conclusions. High levels of TAMs in TIF or absence of histologic tumor necrosis are associated with a significantly improved recurrence-free and overall survival of patients with iCC. These results suggest TAMs and necrosis as valuable prognostic markers in routine histopathologic evaluation, and might indicate more individualized therapeutic strategies.

Cardiopreventive effect of ethanolic extract of Date Palm Pollen against isoproterenol induced myocardial infarction in rats through the inhibition of the angiotensin-converting enzyme

The present study aimed to examine the putative preventive effect of the ethanolic extract Date Palm Pollen (DPP, Phoenix dactylifera L., family Arecaceae) on isoproterenol-induced myocardial infarction (MI) in rats. Twenty four rats were randomly divided into four groups including control. They were treated with DPP extract (400mg/kg) and clopidogrel (0.2mg/kg) for 7days followed by myocardial injury induction using subcutaneous isoproterenol (100mg/kg) with an interval of 24h for two days (6th and 7th day). Administration of isoproterenol exhibited indicative changes in the ECG pattern evidenced by significant elevation of ST-segment and cardiac injury markers viz.; troponin-T, creatine phosphokinase (CPK), alanine aminotransferase (ALT) and lactate dehydrogenase (LDH) by 315%, 71%, 64% and 170%, respectively as compared to control. Additionally, the angiotensin-converting enzyme (ACE) activity in plasma was increased by 33% associated to histological myocardial necrosis. However, pre-co-treatment with DPP extract improved the cardiac biomarkers injury, normalized cardiac function indices and prevented the ventricular remodeling process through inhibition of ACE activity by 34% and the inhibition of the generation of radical oxygen species. Extensive characterization of this DPP extract using LC-HRMS revealed numerous flavonoids and phenols compounds which could be endowed with cardiopreventive actions. Overall, these results proved that DPP extract has preventive effects on cardiac remodeling process.

Non-contrast-enhanced T1 -weighted MRI of myocardial radiofrequency ablation lesions.

To demonstrate imaging of radiofrequency ablation lesions with non-contrast-enhanced T1 -weighted (T1w) MRI. Fifteen swine underwent left ventricular ablation followed by MRI using different preparations: endocardial or epicardial ablation of naïve animal, or endocardial ablation of animal with myocardial infarction. Lesion imaging was performed using free-breathing, non-contrast-enhanced, T1w sequence with long inversion time (TI). Also acquired were T1 maps and delayed contrast-enhanced (DCE) imaging. Hearts were excised for ex vivo imaging, and sliced for gross pathology and histology. All ablations were visibly enhanced in non-contrast-enhanced T1w imaging using TI = 700 ms. T1w enhancement agreed with regions of necrosis in gross pathology and histology. Enhanced lesion cores were surrounded by dark bands containing contraction band necrosis, hematoma, and edema. In animals with myocardial infarction, chronic scar was hypointense in T1w, whereas acute ablations were enhanced, allowing discrimination between chronic scar and acute lesions, unlike DCE. Contrast was sufficient to create 3D volume renderings of lesions after minor postprocessing. Non-contrast-enhanced T1w imaging with long TI promises to be an effective method for visualizing necrosis within radiofrequency ablation lesions. Enhancement is more specific and stationary than that from DCE. The imaging can be repeated as needed, unlike DCE, and may be especially useful for assessing ablations during or after a procedure. Magn Reson Med 79:879-889, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

Atorvastatin does not protect against ischemia-reperfusion damage in cholestatic rat livers

BackgroundExtrahepatic cholestasis sensitizes the liver to ischemia/reperfusion (I/R) injury during surgery for perihilar cholangiocarcinoma. It is associated with pre-existent sterile inflammation, microvascular perfusion defects, and impaired energy status. Statins have been shown to protect against I/R injury in normal and steatotic mouse livers. Therefore, the hepatoprotective properties of atorvastatin were evaluated in a rat model of cholestatic I/R injury.MethodsMale Wistar rats were subjected to 70% hepatic ischemia (during 30 min) at 7 days after bile duct ligation. Rats were randomized to atorvastatin treatment or vehicle-control in three test arms: (1) oral treatment with 5 mg/kg during 7 days after bile duct ligation; (2) intravenous treatment with 2.5, 5, or 7.5 mg/kg at 24 h before ischemia; and (3) intravenous treatment with 5 mg/kg at 30 min before ischemia. Hepatocellular damage was assessed by plasma alanine aminotransferase (ALT) and histological necrosis.ResultsI/R induced severe hepatocellular injury in the cholestatic rat livers (~10-fold increase in ALT at 6 h after I/R and ~30% necrotic areas at 24 h after I/R). Both oral and intravenous atorvastatin treatment decreased ALT levels before ischemia. Intravenous atorvastatin treatment at 5 mg/kg at 24 h before ischemia was the only regimen that reduced ALT levels at 6 h after reperfusion, but not at 24 h after reperfusion. None of the tested regimens were able to reduce histological necrosis at 24 h after reperfusion.ConclusionPre-treatment with atorvastatin did not protect cholestatic livers from hepatocellular damage after I/R. Clinical studies investigating the role of statins in the protection against hepatic I/R injury should not include cholestatic patients with perihilar cholangiocarcinoma. These patients require (pharmacological) interventions that specifically target the cholestasis-associated hepatopathology.

Radiopaque Hemocompatible Ruminant-Sourced Gut Material with Antimicrobial Physiognomies for Biomedical Applications in Diabetics.

This study comprises the fabrication of a radiopaque gut material with its mechanical properties conforming to the US Pharmacopeia guidelines giving an antimicrobial advantage for suture application, especially in conditions such as diabetes mellitus, which has a high wound infection rate. Schiff base cross-linking iodination of the material is evinced by the spectroscopic studies, and antimicrobial properties owing to released iodine are evinced through in vitro studies. Modified gut sutures demonstrated favorable physicomechanical features such as appropriate tensile strength (440 ± 20 MPa) and knot strength (270 ± 20) alongside a mean radiopacity value of 139.0 ± 10 in comparison with that of the femoral shaft with 160 ± 10. The diabetic model showed absence of clinical signs of infection, supported by wound swab culture and the absence of necrosis in histology. Hemocompatibility studies evinced the absence of contact platelet activation and hemolysis alongside the customary coagulation response. These promising results highlight the stimulating potential of the process in the development of biomedical applications, necessitating persistent studies for its evidence-based applicability, particularly in diabetic patients.

Protective role of p53 in acetaminophen hepatotoxicity

p53 is a tumor suppressor with a pro-death role in many conditions. However, in some contexts, evidence supports a pro-survival function. p53 has been shown to be activated in acetaminophen (APAP) toxicity but the impact of this on toxicity is uncertain. In the present study, we have found that p53 plays a protective role in APAP-induced liver injury. We inhibited p53 using three different approaches in mice, pifithrin-α (PFTα), knockdown of p53 expression with antisense oligonucleotide, and p53 knockout. Mice were treated with APAP (300mg/kg) i.p. and after 24h in all three conditions, the liver injury was more severe as reflected in higher ALT levels and great area of necrosis in histology of the liver. Conversely, a p53 activator, nutlin-3a, decreased the liver injury induced by APAP. In the p53 inhibition models, enhanced sustained JNK activation was seen in the early time course, while the JNK was suppressed with the p53 activator. In conclusion, p53 plays a novel protective role in APAP induced liver injury through inhibiting the activation of JNK, a key mediator in APAP-induced oxidative stress.

Radiological response and inflammation scores predict tumour recurrence in patients treated with transarterial chemoembolization before liver transplantation.

AIMTo investigate the prognostic value of the radiological response after transarterial chemoembolization (TACE) and inflammatory markers in patients affected by hepatocellular carcinoma (HCC) awaiting liver transplantation (LT).METHODSWe retrospectively evaluated the preoperative predictors of HCC recurrence in 70 patients treated with conventional (n = 16) or doxorubicin-eluting bead TACE (n = 54) before LT. The patient and tumour characteristics, including the static and dynamic alpha-fetoprotein, neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio (PLR) measurements, were recorded. Treatment response was classified according to the modified Response Evaluation Criteria in Solid Tumours (mRECIST) and the European Association for the Study of the Liver (EASL) criteria as complete response (CR), partial response (PR), stable disease or progressive disease. After examination of the explanted livers, histological necrosis was classified as complete (100% of the cumulative tumour area), partial (50%-99%) or minimal (< 50%) and was correlated with the preoperative radiological findings.RESULTSAccording to the pre-TACE radiological evaluation, 22/70 (31.4%) and 12/70 (17.1%) patients were beyond Milan and University of San Francisco (UCSF) criteria, respectively. After TACE procedures, the objective response (CR + PR) rates were 71.4% and 70.0% according to mRECIST and EASL criteria, respectively. The agreement between the two guidelines in defining the radiological response was rated as very good both for the overall and target lesion response (weighted k-value: 0.98 and 0.93, respectively). Complete and partial histological necrosis were achieved in 14/70 (20.0%) and 28/70 (40.0%) patients, respectively. Using histopathology as the reference standard, mRECIST criteria correctly classified necrosis in 72.9% (51/70) of patients and EASL criteria in 68.6% (48/70) of cases. The mRECIST non-response to TACE [Exp(b) = 9.2, p = 0.012], exceeding UCSF criteria before TACE [Exp(b) = 4.7, p = 0.033] and a preoperative PLR > 150 [Exp(b) = 5.9, p = 0.046] were independent predictors of tumour recurrence.CONCLUSIONThe radiological response and inflammatory markers are predictive of tumour recurrence and allow the proper selection of TACE-treated candidates for LT.

Role of Periapical Diseases in Medication-Related Osteonecrosis of the Jaws.

Objective The present study aimed to investigate the role of periapical diseases in inducing medication-related osteonecrosis of the jaws (MRONJ) using an ovariectomized (OVX) mice model. Materials and Methods Twenty C57BL/6N female mice were randomly assigned to two groups. All mice were subjected to bilateral ovariectomy and then treated with oncologic dose of zoledronic acid (ZA) or vehicle for twelve weeks. Eight weeks after commence of drug administration, a pulpal exposure (PE) operation was performed on the first right lower molar to induce periapical periodontitis; the contralateral non-PE tooth was used as control. All animals were sacrificed four weeks after pulpal exposure, and the mandibles were harvested for radiological and histomorphometrical analysis. Results Micro computed tomography (μ-CT) examination demonstrated that periapical diseases significantly increased alveolar bone resorption, and the resorption was greatly attenuated by ZA treatment. Concurrent ZA therapy significantly increased bone density and histological osteocyte necrosis in the presence of periapical lesions. Conclusion ZA treatment reduced bone absorption resulting from periapical disease but increased the risk of developing MRONJ in the ovariectomized mouse model.

Isolated limb perfusion for the management limb threatening soft tissue sarcomas: The role of histological type on clinical outcomes

BackgroundHyperthermic isolated limb perfusion (HILP) is an effective neoadjuvant treatment to avoid amputation in patients with locally advanced extremity soft tissue sarcomas (STS). We aimed to investigate whether STS histological type plays a role in predicting clinical outcomes. MethodsThis study reports a retrospective analysis of 125 patients with limb threatening STS (liposarcoma, n = 41; malignant peripheral nerve sheath tumor, n = 20; leiomyosarcoma, n = 20; miscellany, n = 44), who underwent HILP from 1990 through 2015 at our institution. The following endpoints were evaluated: tumor response (assessed by radiological imaging and histology), limb sparing rate, local progression-free survival (LPFS) and overall survival (OS). ResultsOn average, overall (complete + partial) tumor response was significantly greater in patients affected with liposarcoma as compared to those with other histotypes (radiological response rate: 38/41, 92.7% vs 66/84, 78.6%, P-value: 0.048; mean histological necrosis: 83.6% vs 52.9%, P < 0.0001). Limb sparing rate was also higher among patients with liposarcoma as compared to other histotypes (39/41, 95.1% vs 62/84, 73.8%, P-value: 0.005). As regards survival, LPFS was similar across tumor types, whereas OS resulted significantly worse in patients with limb leiomyosarcoma (log-rank P-value: 0.009). ConclusionsHILP is a very effective treatment modality for limb threatening STS. In our series, liposarcoma appears to be the histological type most sensitive to HILP in terms of tumor response and thus limb sparing, which might help clinicians in the patient selection process.

The starting point for bisphosphonate-related osteonecrosis of the jaw: Alveolar bone or oral mucosa? A randomized, controlled experimental study.

Although over a decade has passed since first introduction of BRONJ, the exact pathophysiology of this disease is still unclear. The present experimental study aimed to determine whether the oral mucosa or alveolar bone serves as the starting point for BRONJ development. Sixty male Wistar rats were randomly assigned into study and control groups (each, n=30), and received intraperitoneal injection of 0.06mg/kg zoledronate and saline, respectively, once a week for 12 weeks. At the end of the week 4 of the experiment, all 60 rats underwent unilateral mandibular first molar extraction. A 4mm defect was made in the contralateral canine alveolar mucosa. At the end of the experiment, rats were sacrificed, and the three areas of interest including extraction, soft tissue defect, and the non-intervention (canine area on the same side of extraction) sites were assessed clinically for presence of bone exposure/fistula, and histologically for status of bone remodeling (only at extraction site) and osteonecrosis. In the study group, the frequency of bone exposure/fistula was 80%, 0%, and 0%; and the rate of histological bone necrosis was 83.3%, 20%, and 0%; at the extraction, soft tissue defect, and non-intervention sites, respectively. No clinical and histological sign of bone necrosis was found in the control group. Normal bone remodeling was observed in 0% and 100% of the extraction sockets in the study and control groups, respectively. Injury to alveolar bone was a stronger trigger for BRONJ development compared to oral mucosal damages.

Prognostic serum markers in patients with high-grade upper tract urothelial carcinoma

IntroductionThe role of preoperative serum-based markers in predicting survival outcomes of patients has been reported for several cancer types; however, their association with upper tract urothelial carcinoma (UTUC) prognosis is unclear. We evaluated the role of systemic serum-based markers in predicting adverse pathological features and survival outcomes in patients surgically treated for high-grade (HG) UTUC. MethodsWe retrospectively reviewed all patients undergoing surgery for HG UTUC between June 2006 and July 2013 at our institution. Comprehensive clinicopathologic data and preoperative serum-based markers including hemoglobin, white blood cell count, platelet count, serum albumin, calcium, and liver function tests were recorded. Associations of serum markers with pathologic features and recurrence-free survival (RFS) were determined by logistic and Cox regression analyses, respectively. The concordance index for the oncologic outcomes model was determined. ResultsIn total, 101 patients were identified with a median follow-up of 18.5 months (range: 1–74mo). In all, 60% of patients had pT2 or less and 11% had nodal metastases. Preoperative elevated alkaline phosphatase (ALP) (≥116IU/l) was associated with multiple adverse pathologic features including advanced T stage, lymphovascular invasion, and histologic necrosis. On univariate analysis, serum markers independently associated with RFS included hemoglobin≤12.9 (hazards ratio [HR] = 2.51; 95% CI: 1.17–5.36, P = 0.018), albumin≤4g/dl (HR = 4.4; 95% CI: 2.04–9.30; P<0.0001), ALP≥116U/l (HR = 13.3; 95% CI: 5.3–33.52, P<0.0001), alanine transaminase≥27 (HR = 2.63, 95% CI: 1.11–6.21, P = 0.028), serum aspartate transaminase≥20 (HR = 2.21, 95% CI: 1.04–4.69, P = 0.038), and corrected calcium≥9.3 (HR = 2.45, 95% CI: 1.01–5.93, P = 0.047). The 2 strongest predictors, albumin and ALP, were combined to form an AA score (range: 0–2), which improved the baseline preoperative clinical model concordance index for prediction of RFS from 0.626 to 0.799. ConclusionIn HG UTUC, elevated preoperative ALP was associated with adverse pathologic features. Additionally, elevated ALP and low albumin were independently associated with worse RFS and overall survival. These serum-based markers are often measured in the preoperative workup of UTUC, and thus they can be included in future prognostic models to risk stratify patients.

The incidence of adverse pathologic characteristics in small renal masses as size increases.

596 Background: The AUA guidelines include active surveillance (AS) as an option for patients with the cT1a renal mass (≤4 cm). We evaluate how increasing tumor size (≤4 cm) correlates to the incidence of adverse pathologic features (APF) found on nephrectomy. Methods: We queried a single institution database of nephrectomy specimens from subjects undergoing surgery for renal cell carcinoma (RCC). From a total of 898 consecutive cases, 389 patients had primary tumors that were ≤4 cm and N0, M0. All cases were centrally reviewed for the following adverse pathologic features: high nuclear grade (Fuhrman grade 3 or 4), lymphovascular invasion (LVI), histologic tumor necrosis, sarcomatoid features, rhabdoid features, papillary type II histology and advanced stage (≥pT3). Tumor size categories were compared in 1 cm increments. Relationships between the variables were analyzed by chi-square, Fisher’s exact, and ANOVA tests. Results: There was a significant increase in tumor grade (p=0.006) and stage (p=0.04) seen as size increased. APF were found in 157 (40.4%) of tumors ranging from 22.2% for tumors ≤1 cm to 50.8% of tumors &gt;3 to ≤4. There was a significant increase in the presence of one or more of any APF as size increased (p=0.013). Conclusions: Tumors ≤4 cm that could be considered for AS still show frequent aggressive characteristics at nephrectomy. As over half of tumors 3-4 cm have APF, caution is advised when placing patients with larger tumors on AS. Renal tumor biopsy may identify several aggressive histologic characteristics and could be considered to aid the selection of patients considering AS. [Table: see text]

Chronic Paraspinal Muscle Injury Model in Rat.

ObjectiveThe objective of this study is to establish an animal model of chronic paraspinal muscle injury in rat.MethodsFifty four Sprague-Dawley male rats were divided into experimental group (n=30), sham (n=15), and normal group (n=9). Incision was done from T7 to L2 and paraspinal muscles were detached from spine and tied at each level. The paraspinal muscles were exposed and untied at 2 weeks after surgery. Sham operation was done by paraspinal muscles dissection at the same levels and wound closure was done without tying. Kyphotic index and thoracolumbar Cobb's angle were measured at preoperative, 2, 4, 8, and 12 weeks after the first surgery for all groups. The rats were sacrificed at 4, 8, and 12 weeks after the first surgery, and performed histological examinations.Results At 4 weeks after surgery, the kyphotic index decreased, but, Cobb's angle increased significantly in the experimental group (p<0.05), and then that were maintained until the end of the experiment. However, there were no significant differences of the kyphotic index and Cobb's angle between sham and normal groups. In histological examinations, necrosis and fibrosis were observed definitely and persisted until 12 weeks after surgery. There were also presences of regenerated muscle cells which nucleus is at the center of cytoplasm, centronucleated myofibers.ConclusionOur chronic injury model of paraspinal muscles in rats shows necrosis and fibrosis in the muscles for 12 weeks after surgery, which might be useful to study the pathophysiology of the degenerative thoracolumbar kyphosis or degeneration of paraspinal muscles.

Low Dose Acetaminophen Induces Reversible Mitochondrial Dysfunction Associated with Transient c-Jun N-Terminal Kinase Activation in Mouse Liver.

Acetaminophen (APAP) overdose causes hepatotoxicity involving mitochondrial dysfunction and c-jun N-terminal kinase (JNK) activation. Because the safe limit of APAP dosing is controversial, our aim was to evaluate the role of the mitochondrial permeability transition (MPT) and JNK in mitochondrial dysfunction after APAP dosing considered nontoxic by criteria of serum alanine aminotransferase (ALT) release and histological necrosis invivo. C57BL/6 mice were given APAP with and without the MPT inhibitor, N-methyl-4-isoleucine cyclosporin (NIM811), or the JNK inhibitor, SP600125. Fat droplet formation, cell viability, and mitochondrial function invivo were monitored by intravital multiphoton microscopy. Serum ALT, liver histology, total JNK, and activated phospho(p)JNK were also assessed. High APAP (300 mg/kg) caused ALT release, necrosis, irreversible mitochondrial dysfunction, and hepatocellular death. By contrast, lower APAP (150 mg/kg) caused reversible mitochondrial dysfunction and fat droplet formation in hepatocytes without ALT release or necrosis. Mitochondrial protein N-acetyl-p-benzoquinone imine adducts correlated with early JNK activation, but irreversible mitochondrial depolarization and necrosis at high dose were associated with sustained JNK activation and translocation to mitochondria. NIM811 prevented cell death and/or mitochondrial depolarization after both high and low dose APAP. After low dose, SP600125 decreased mitochondrial depolarization. In conclusion, low dose APAP produces reversible MPT-dependent mitochondrial dysfunction and steatosis in hepatocytes without causing ALT release or necrosis, whereas high dose leads to irreversible mitochondrial dysfunction and cell death associated with sustained JNK activation. Thus, nontoxic APAP has the potential to cause transient mitochondrial dysfunction that may synergize with other stresses to promote liver damage and steatosis.

La phonomyographie comme méthode non invasive de détection et de suivi du syndrome de loge – évaluation sur un modèle de syndrome de loge chez le rat

Introduction Phonomyography (PMG) is a noninvasive acoustic technique by which microphones placed on the skin surface detect the low-frequency sounds emitted by muscle upon contraction. Presently, there is no reliable noninvasive continuous monitoring technique for the detection of acute compartment syndrome (ACS), a traumatic condition seen in military and civilian trauma victims. The phase 1 of this study (ischemia induction of 15 adult rat legs through direct iliac vessel clamping) has already shown promising results with decrease in the signal amplitude of PMG proportional to ischemia duration. The goal of the phase 2 is to confirm the ability of PMG to detect early changes in muscle contraction during ACS in a rat model. Material Adult Sprague rats were used for the phase 2 of the experiment. Methods In 14 adult Sprague rats, after general anesthesia induction, an acute compartment syndrome was induced by infusion of a physiologic saline solution into the left posterior calf compartment (direct ACS induction model), while the right posterior calf compartment was used as a control. At intervals of 10 minutes, for a maximum of 6 hours, the sciatic nerve of each leg was stimulated with a nerve stimulator, and the PMG acoustic signal recorded. ACS duration was different for each group of 3 rats (30 min, 1 h, 2 h, 4 h and 6 h). At the end of the procedure, compartment was released with fasciotomy and rats awakened after skin closure. At day 4, calf muscle biopsies were harvested and sent to pathology. Results We were able to get data for 14 rats (one rat in the 6 h group died at the end of the procedure). The PMG showed a decrease in the amplitude of the low-frequency signal emitted from injured muscle of the ACS limb, which correlated with the duration of muscle and nerve injury ischemia and histologic necrosis. At time t = 4 h, there was a statistically significant ( P n = 5 + P = 0.043). Discussion These findings further confirm the results obtained during the phase 1 (ischemia induction through iliac vessel clamping) and the potential of PMG as a continuous noninvasive detection method for ACS, by showing an alteration in the acoustic signal emitted by the muscles of an injured ischemic limb. Conclusion PMG is a promising device (patented) for continuous noninvasive monitoring of suspected ACS. The next step is to evaluate its accuracy with patient operated on for leg fracture, compared to direct pressure measurement.

Prognostic Value of 18-Fluorodeoxyglucose-Positron Emission Tomography After Transarterial Chemoembolization in Patients With Hepatocellular Carcinoma Undergoing Orthotopic Liver Transplantation

IntroductionThe aim of this study was to analyze the correlation between 18-FDG positron emission tomography (PET)/computed tomography (CT), histological necrosis, and prognosis after transarterial chemoembolization (TACE) for hepatocellular carcinoma (HCC) patients undergoing orthotopic liver transplantation (OLT). PatientsFrom January 2007 through December 2013, 81 patients with HCC and liver cirrhosis were included in our liver transplantation program. For this study we selected patients who underwent 18-FDG PET/CT pre-TACE and post-TACE. All patients underwent liver transplantation within 8 weeks after PET/CT. ResultsTwenty patients with a median age of 58 years (range, 46–69 years) underwent an 18-FDG PET/CT before and after TACE. The median Standardized Uptake Value (SUV) before TACE was 3.8 (range, 2.6–8.7), with a median post-TACE SUV of 0% (range, 0–4). Among patients whose post-TACE SUV decreased to <3, >70% necrosis was observed upon study of a hepatectomy sample, with a survival rate of 100% and 80% at 1 and 3 years, respectively. ConclusionIn conclusion, performance of an 18-FDG PET/CT before and after TACE with comparison of SUV values among patients with HCC awaiting OLT provided valuable information regarding the effectiveness of TACE.